Filamentous deposits of hyperphosphorylated tau proteins are a major pathological hallmark of a large number of dementing disorders, such as Alzheimer's disease (AD) and frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). The predominant isoform of protein phosphatase 2A (PP2A), ABaC, is present on the microtubule (MT) cytoskeleton, binds to tau, and regulates the phosphorylation state and MT binding/stabilizing activities of tau in cells. The primary goals of the proposed studies are to further characterize the structural and functional interrelationships that exist among ABaC, tau, and MTs, and address the hypothesis that their disruption promotes the accumulation of hyperphosphorylated forms of tau in all tauopathies. The first aim will focus on establishing major properties of PP2A/tau and PP2A/MT interactions in vitro and in cells. Their functional significance for MT stability and the distribution and phosphorylation of tau proteins will then be investigated in Aim 2. Expression of PP2A or tau protein mutants, and novel phosphorylation-sensitive tau antibodies will be used to address the relevance of PP2A/tau/MT interactions in chosen neuronal and non-neuronal cellular models. In Aim 3, the distribution of ABaC and tau proteins will be compared by immunohistochemistry in human brain regions from non-demented controls, AD, and other tauopathies, in order to assess whether changes in PP2A expression levels are associated with the presence of hyperphosphorylated tau in tau-positive lesions. In addition, biochemical methods will be used to correlate these results with the expression, activity and carboxymethylation levels of PP2A determined in the same brain regions. These studies should provide new insights into the functional role of PP2A in the regulation of tau and the MT cytoskeleton, and in the regulation of PP2A itself. Elucidating the mechanisms that govern normal tau functions and regulation is a key step towards understanding the processes that lead to the tau abnormalities, compromised MT functions, and neurodegenerative events in AD and other human tauopathies.